Madhura Kulkarni,1,4 Tuan Zea Tan,1 Nurfarhanah Bte Syed Sulaiman,1 John M. Lamar,2,5 Prashali Bansal,1,6 Jianzhou Cui,1 Yiting Qiao,1 and Yoshiaki Ito1,3.
1Cancer Science Institute, NUS, Singapore.
2Transnational Cancer Research Centre, Prashanti Cancer Care Mission and Indian Institute of Science Education and Research, Pune, India.
3Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
4Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
5Max Planck Institute for Developmental Biology, Tübingen, Germany.
6Yong Loo Lin Professor in Medical Oncology, NUS, Singapore.
Hippo pathway target, YAP has emerged as an important player in solid tumor progression. Here, we identify RUNX1 and RUNX3 as novel negative regulators of oncogenic function of YAP in the context of breast cancer. RUNX proteins are one of the first transcription factors identified to interact with YAP. RUNX1 or RUNX3 expression abrogates YAP-mediated pro-tumorigenic properties of mammary epithelial cell lines in an interaction dependent manner. RUNX1 and RUNX3 inhibit YAP-mediated migration and stem-ness properties of mammary epithelial cell lines by co-regulating YAP-mediated gene expression. Analysis of whole genome expression profiles of breast cancer samples revealed significant co-relation between YAP-RUNX1/RUNX3 expression levels and survival outcomes of breast cancer patients. High RUNX1/RUNX3 expression proved protective towards YAP-dependent patient survival outcomes. High YAP in breast cancer patients’ expression profiles co-related with EMT and stem-ness gene signature enrichment. High RUNX1/RUNX3 expression along with high YAP reflected lower enrichment of EMT and stem-ness signatures. This antagonistic activity of RUNX1 and RUNX3 towards oncogenic function of YAP identified in mammary epithelial cells as well as in breast cancer expression profiles gives a novel mechanistic insight into oncogene-tumor suppressor interplay in the context of breast cancer progression. The novel interplay between YAP, RUNX1 and RUNX3 and its significance in breast cancer progression can serve as a prognostic tool to predict cancer recurrence.
EMT; RUNX1 and RUNX3; YAP; breast cancer; stem-ness